CN102791256A - Nanoparticulate candesartan cilexetil compositions, process for the preparation thereof and pharmaceutical compositions containing them - Google Patents
Nanoparticulate candesartan cilexetil compositions, process for the preparation thereof and pharmaceutical compositions containing them Download PDFInfo
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- CN102791256A CN102791256A CN2010800362962A CN201080036296A CN102791256A CN 102791256 A CN102791256 A CN 102791256A CN 2010800362962 A CN2010800362962 A CN 2010800362962A CN 201080036296 A CN201080036296 A CN 201080036296A CN 102791256 A CN102791256 A CN 102791256A
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- candesartan
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- candesartan cilexetil
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
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- A—HUMAN NECESSITIES
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- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
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- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T428/00—Stock material or miscellaneous articles
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Abstract
The present invention is directed to nanostructured (nanoparticulated) Candesartan or its pharmaceutically acceptable ester, preferable Candesartan Cilexetil, or co-crystal compositions, process for the preparation thereof and pharmaceutical compositions containing them. The nanoparticles of Candesartan or its pharmaceutically acceptable ester, preferable Candesartan Cilexetil, or co-crystal according to the invention have an average particle size of less than about 500 nm. Candesartan Cilexetil is a prodrug, is hydrolyzed to Candesartan during absorption from the gastrointestinal tract. Candesartan is a selective AT1 subtype angiotensin II receptor antagonist.
Description
Technical field
The present invention relates to (nano-particle) Candesartan or the acceptable ester of its pharmacy, preferred Candesartan Cilexetil or cocrystallization compositions, its preparation method of nanostructured and comprise their pharmaceutical composition.
The nano-particle of Candesartan of the present invention or the acceptable ester of its pharmacy, preferred Candesartan Cilexetil or cocrystallization has the particle mean size less than 500nm.Candesartan Cilexetil is a prodrug, absorbs through gastrointestinal to be hydrolyzed to Candesartan.Candesartan is a kind of selectivity AT1 subtype angiotensin II receptor antagonist.
Background technology
A. about the background of nano-particle formation/generation
The exploitation that is used for the nano-particle of pharmaceutical applications relates to the appearance of the new technique that is used to develop the delivery system special solution.Delivery system should influence medicine energetically or other are about chemical substance absorption in vivo, distribution, metabolism and excretory speed.In addition, delivery system should make medicine combine its target receptor and influence the signal conduction and the activity of this receptor.Medicine is passed drug material should be compatible with certain drugs, be easy to combine and can after use, be degraded into the part through normal excretion pathway metabolism or discharge.
Diverse ways is the active component (API) of production form of nanoparticles.
Nano-particle and the micron particles compositions for example in US 20080058399, WO 2008030161 and US 20060165806, described.
For example, as well known in the art, can use grinding, homogenize, sedimentation or supercritical fluid technology to prepare the API nano-particle.Also at US 5,718,388, described the method for preparing of Nanoparticulate compositions among the US 5,862,999, US 5,665,331, US 5,543,133, US 5,534,270.
The background of B. relevant Candesartan Cilexetil
Candesartan Cilexetil is non-peptide, chemically is being described as (±)-1-ethoxy-2-ethyoxyl-1-[right-(adjacent 1H-tetrazole radical-5-base phenyl) benzyl]-7-benzimidazole carboxylate, carbonic acid cyclohexyl (ester).
Its chemical formula is C
33H
34N
6O
6, its structural formula is:
Candesartan Cilexetil is that molecular weight is that 610.67 white is to pale powder.It is in fact water insoluble and be slightly soluble in methanol.Candesartan Cilexetil is the racemic mixture that is included in a chiral centre on the cyclohexyloxy carbonyl oxygen base ethoxycarbonyl.After Orally administered, Candesartan Cilexetil forms active medicine, promptly achiral Candesartan through the hydrolysis on ester bond.
Its method for preparing has for example been described in WO/2008/035360, WO/2007/147514, WO/2008/062047.
Candesartan Cilexetil obtains as Orally administered tablet; It comprises the Candesartan Cilexetil of 4mg, 8mg, 16mg or 32mg, and comprises following non-active ingredient: hydroxypropyl cellulose, Polyethylene Glycol, lactose, corn starch, carboxymethylcellulose calcium and magnesium stearate.Ferrum oxide (bronzing) joins in 8-mg, 16-mg and the 32-mg tablet as coloring agent.
Pharmacological property
Candesartan Cilexetil becomes the Candesartan of biologically active, a kind of selectivity AT1 subtype angiotensin II receptor antagonist through gastrointestinal absorption rapidly and fully through the ester hydrolysis.Candesartan main (via bile) is not drained in urine and feces with changing.It less becomes through the O-de-ethylation via liver metabolism does not have active metabolite.The elimination half-life of Candesartan is about 9 hours.After single and repetitive administration, the pharmacokinetics that the Candesartan Cilexetil oral dose reaches the Candesartan of 32mg is linearity.Candesartan does not have active metabolite in serum, not accumulate during 1 repeat administration in every day with it.
After Candesartan Cilexetil was used, the absolute bioavailability of Candesartan was estimated as 15%.After taking in tablet, reached serum peak concentration (C in 3-4 hour
Max).The food that has high fat content after Candesartan Cilexetil is used does not influence the bioavailability of Candesartan.
Metabolism and drainage
Total plasma clearance of Candesartan is 0.37mL/min/kg, and renal clearance is 0.19mL/min/kg.When using Candesartan, nearly 26% dosage is not drained in urine with changing when oral.Orally give 1
4Behind the Candesartan Cilexetil of C-labelling, in urine, recover about 33% radioactivity and in feces, recover about 67%.Intravenous gives
14Behind the Candesartan of C-labelling, in urine, recover about 59% radioactivity and in feces, recover about 36%.Bile excretion helps to eliminate Candesartan.
Distribute
The volume of distribution of Candesartan is 0.13L/kg.The Candesartan height combines plasma protein (＞99%) and does not infiltrate erythrocyte.Candesartan PC this protein binding in the scope that RD reaches is constant.In rat, even proved that it also is seldom to cross blood brain barrier that Candesartan has.Prove that also for rat, Candesartan passes through placental barrier and is distributed in the fetus.
Side effect
In all tests of patient (totally 7510), withdraw from by what adverse events caused; Using Candesartan Cilexetil is 3.3% (promptly as the patient's of monotherapy treatment ratio; In 3260 108) and use the patient's of placebo treatment ratio to be 3.5% (that is, 1106 in 39).
The most general reason of drug withdrawal is headache (0.6%) and dizzy (0.3%) in the Candesartan Cilexetil treatment.
Being at least 1% patient in the adverse events that in placebo-contrast clinical trial, takes place treats with Candesartan Cilexetil; Candesartan Cilexetil patient (n=2350) has higher sickness rate than placebo patient (n=1027), comprises backache (3% pair 2%), dizzy (4% pair 3%), upper respiratory tract infection (6% pair 4%), pharyngitis (2% pair 1%) and rhinitis (2% pair 1%).
Because Candesartan and indissolubility and the low bioavailability of Candesartan Cilexetil in water; Need improve lipotropy/bioavailability/increase absorption/minimizing side effect/minimizing dosage/begin sooner effect in the art, so that overcome the relevant problem of candesartan cilexetil ester formulation with existing routine.In addition, can solve these problems to reduce first pass effect or to change the Candesartan Cilexetil metabolism through finishing.Except that the Candesartan Cilexetil conventional formulation, transdermal is used also can shorten the required time of Candesartan Cilexetil desired effects that reaches.The present invention has satisfied this demand.
Summary of the invention
The invention describes nano-particle Candesartan, the acceptable ester of its pharmacy, preferred Candesartan Cilexetil and the cocrystallization compositions of dosage of side effect/reduction of absorption and the dissolution rate/minimizing of lipotropy/bioavailability/increase with raising.
As institute's illustration among the following embodiment, the combination that is not each stabilizing agent all can cause the stabilized nano granule to form.Discovery can be through preparing stable Candesartan or the acceptable ester of its pharmacy, preferred Candesartan Cilexetil or cocrystallization nano-particle based on the continuous flow method of microfluid, the stabilizing agent that use is selected.
The present invention comprises the stabilized nano particulate composition, and it comprises:
(a) have less than the nano-particle Candesartan of about 500nm particle mean size or the acceptable ester of its pharmacy, preferred Candesartan Cilexetil or cocrystallization; With
(b) at least a stabilizing agent.
Wherein, in continuous flow reactor, prepare compositions.
Compositions of the present invention prepares in continuous flow reactor, preferably in the continuous flow reactor based on microfluid, prepares.
In compositions of the present invention, the particle mean size of Candesartan or the acceptable ester of its pharmacy, preferred Candesartan Cilexetil or cocrystallization is 500nm-50nm.
In compositions of the present invention: (a) amount of Candesartan or the acceptable ester of its pharmacy, preferred Candesartan Cilexetil or cocrystallization be selected from that about 99.5%-is about 0.001%, about 95%-about 0.1% and about 0.5% weight of about 90%-; Sum total and weight with Candesartan or the acceptable ester of its pharmacy, preferred Candesartan Cilexetil or cocrystallization and at least a stabilizing agent are benchmark, do not comprise other excipient; (b) amount of stabilizing agent is selected from about 99.999% weight of about 0.5%-, about 99.9% weight of about 5.0%-and about 99.5% weight of about 10%-; Total merging dry weight with Candesartan or the acceptable ester of its pharmacy, preferred Candesartan Cilexetil or cocrystallization and at least a stabilizing agent is a benchmark, does not comprise other excipient; Or (c) (a) and combination (b).
In compositions of the present invention, Candesartan or the acceptable ester of its pharmacy, preferred Candesartan Cilexetil or cocrystallization can use with crystalline phase, amorphous phase, half hitch crystalline phase, half amorphous phase and cocrystallization and any polymorphous form of mixtures thereof.
In order to prepare compositions of the present invention, can use stabilizing agent, comprise nonionic, anionic, cationic, ion-type and zwitterionic surfactant.Can also use the combination of more than one stabilizing agents among the present invention, can be used for useful stabilizing agent of the present invention and comprise but be not limited to known organic and inorganic drug excipient.This excipient comprises various polymer, low-molecular weight oligo body, natural product and surfactant.
The representational instance of stabilizing agent comprises hydroxypropyl emthylcellulose, hydroxypropyl cellulose, gathers (vinylpyrrolidone), sodium lauryl sulphate, gelatin, glucosan, stearic acid, glyceryl monostearate, cetostearyl alcohol, sorbitan ester, castor oil derivatives, polyoxyethylene sorbitan fatty acid ester class (Tween that for example is purchased
product, for example Tween
20 and Tween
80 (ICI Speciality Chemicals); Polyethylene glycols (for example Carbowax
3550 and 934 (Union Carbide), based on the polymer that gathers (methyl) acrylic ester and copolymer (Eudargit
), with l-vinyl-2-pyrrolidone vinyl-acetic ester polymer (PVP/VA copolymer), dodecylbenzene sodium sulfonate, tocopherol polyethyleneglycol succinate class, GREMAPHOR GS32 and derivant thereof, Myrj 45 class, methylcellulose, hydroxyethyl-cellulose, CAP, polyvinyl alcohol (PVA), with the 4-(1 of oxirane and formaldehyde; 1; 3; The 3-tetramethyl butyl)-cascophen (being also referred to as tyloxapol, alevaire (superione) and TritonX), poloxamer class (for example Pluronics, it is the block copolymer of oxirane and expoxy propane); The polyamine class (for example Tetronic is also referred to as polyamine, its be derived from continuous four functional blocks copolymers of addition expoxy propane and oxirane to ethylenediamine (BASF Wyandotte Corporation, Parsippany, nJ.); PEG-phospholipid, PEG-cholesterol, PEG-cholesterol derivative, PEG-vitamin A, PEG-vitamin E, lysozyme, gather (2-ethyl-2-oxazoline), gather the randomcopolymer of (methyl vinyl ether), vinyl pyrrolidone and vinylacetate, for example Plasdone S630 etc.
The instance of useful ion-type stabilizing agent is including, but not limited to the chemical compound of polymer, biopolymer, polysaccharide, cellulosics, alginate, phospholipid and non-polymer, for example the amphion stabilizing agent, gather-the n-picoline, chlorination anthryl pyridine, cationic phospholipid, chitosan, polylysine, polyvinyl imidazole, polybrene, polymethyl methacrylate, bromination trimethylammonium (PMMTMABr), benzalkonium chloride, hexadecyltrimethylammonium bromide, bromination hexyl desyl,a-phenyl phenacyl tripotassium ammonium (HDMAB) and gather (vinylpyrrolidone)-2-dimethylaminoethyl methacrylate dimethyl disulfide acid esters.
The advantage of the present composition is including, but not limited to: the tablet that (1) is less or other solid dosage formss size and useful transdermal/topical application; (2) compare with conventional Candesartan Cilexetil dosage form obtain identical pharmacological effect required than low-dose drugs; (3) compare the bioavailability of increase with conventional Candesartan Cilexetil dosage form; (4) improved pharmacokinetic properties; (5) compare the Candesartan or the Candesartan Cilexetil nano-particle dissolution rate of increase with the regular dosage form of identical reactive compound; (6) the improved metabolism of Candesartan or Candesartan Cilexetil nano-particle.
In order to prepare compositions of the present invention, can use such method, comprise that the continuous solvent-anti-solvent deposition or the continuous chemical that use one or more stabilizing agents precipitate to form nano-particle.
Another aspect of the present invention is the method for preparing of Candesartan or the acceptable ester of its pharmacy, preferred Candesartan Cilexetil or the cocrystallization of nanostructured; Be included in the continuous flow reactor, in the presence of acceptable acid of pharmacy or alkali (if desired) can suitably dissolve Candesartan or the acceptable ester of its pharmacy, the preferred candesartan cilexetil ester solution Candesartan of deposition nanostructured or the acceptable ester of its pharmacy, preferred Candesartan Cilexetil or cocrystallization from what comprise one or more stabilizing agents.
As continuous flow reactor, can use continuous flow reactor based on microfluid.
The used continuous flow reactor based on microfluid is described in open source literature I.Hornyak, among the Microfluid nanofluid DOI10.1007/s10404-008-0257-9 of B.Borcsek and F.Darvas.
Preferably carry out this method through the following step: (1) is dissolved in suitable solvent with Candesartan or the acceptable ester of its pharmacy, preferred Candesartan Cilexetil and one or more optional stabilizing agents; (2) will join from the preparation of step (1) and comprise one or more stabilizing agents and if desired in the solution of the acceptable acid of pharmacy or alkali; (3) deposition is from the preparation of step (2).
Perhaps can carry out through the following step: (1) is dissolved in suitable solvent with Candesartan or the acceptable ester of its pharmacy, preferred Candesartan Cilexetil and one or more stabilizing agents; (2) will join from the preparation of step (1) and comprise one or more stabilizing agents and if desired in the solution of the acceptable acid of pharmacy or alkali; (3) deposition is from the preparation of step (2).
As solvent, two kinds of different solvents that can use (a) be prone to dissolve to mix each other, wherein Candesartan one of is only soluble in the solvent for use; Or (b) in two steps, use identical solvent, wherein in fact the granule of Candesartan or the acceptable ester of its pharmacy, preferred Candesartan Cilexetil nanostructured, is limited in applied stabilizing agent and is dissolved in used solvent.
This solvent can be dimethyl sulfoxine, ethanol, isopropyl alcohol, oxolane, acetone, methanol, preferred pyridine.
The granularity of nano-particle Candesartan or the acceptable ester of its pharmacy, preferred Candesartan Cilexetil or cocrystallization can receive the influence of solvent for use, flow velocity, Candesartan or the acceptable ester of its pharmacy, preferred Candesartan Cilexetil or cocrystallization-stabilizing agent ratio.
Candesartan or the acceptable ester of its pharmacy, preferred Candesartan Cilexetil or the cocrystallization that another aspect of the present invention relates to solid nano size form is in biological associated media good/instantaneous redispersibility in normal saline solution, the pH=2.5HCl solution for example.
Another aspect of the present invention is to comprise the pharmaceutical composition of stabilized nano granule Candesartan or the acceptable ester of its pharmacy, preferred Candesartan Cilexetil or cocrystallization compositions and optional acceptable auxiliary material of pharmacy.
Can pharmaceutical composition of the present invention be mixed with: (a) be used to be selected from oral, lung, rectum, colon, parenteral, the brain pond, intravaginal, intraperitoneal, eye, ear, part, suck, the using of nose and local application; (b) be selected from liquid dispersion, gel, aerosol, ointment, cream, lyophilized formulations, tablet, capsular dosage form; (c) dosage form that be selected from controlled release preparation, fast thawing preparation, time-delay delivery formulations, prolongs delivery formulations, pulsed delivery formulations and blended rapid release and controlled release preparation; Or (d) (a) and (b) and (c) combination in any.
Can prepare the compositions that is used for solid, liquid, vagina, rectum, part (powder, ointment or drop) or local application etc. through adding dissimilar excipient.
Preferred dosage form of the present invention is solid or liquid (cream/ointment) dosage form, but, also can use any pharmacy acceptable forms.
For oral delivery is gone into human body, can also nano-particle be used as the aqueous dispersion of its final dosage form.This is the mode of sending of after nano-particle forms, further not processing.Yet medicine or polymer poor stability or the taste difference of medicine in aqueous environments possibly mixed solid dosage forms with colloidal solid, promptly mixes capsule and tablet.
Perhaps, can the aqueous dispersion of colloidal solid be mixed solid dosage forms as liquid, for example, form granule through the filler that is fit to being granulated with aqueous colloidal dispersion.Can particles filledly go into capsule or be pressed into tablet this then.Perhaps, through in fluid bed, make dispersion for example as the sugar pill higher slice of carrier, can form the solid form of nano-particle.Can carry out coating steps after the mode of these production labels or granule or pill, to show as the thin membrane coated tablet of final dosage form or the film coating granule in the capsule.
The compositions that is suitable for parenteral injection can comprise the acceptable sterilized water of physiology or non-aqueous solution, dispersion liquid, suspension or Emulsion and be dissolved into the sterilized powder of sterile injectable solution or dispersion liquid again.The water and the examples of non-aqueous carriers that are fit to are diluent, solvent or vehicle; Comprise water, ethanol, polyhydric alcohol (propylene glycol, Polyethylene Glycol, glycerol etc.), its mixture, vegetable oil (for example olive oil) and injectable organosilane ester that is fit to, for example ethyl oleate.For example, can through use the coating dress material for example lecithin, with regard to dispersion through keeping required granularity and through using surfactant to keep suitable flowability.
Be used for Orally administered solid dosage forms including, but not limited to capsule, tablet, pill, powder and granule.In this solid dosage forms, activating agent is mixed with following at least a composition: (a) one or more inert excipients (or carrier), for example sodium citrate or dicalcium phosphate; (b) filler or extender, for example starch, lactose, sucrose, glucose, mannitol and silicic acid; (c) binding agent, for example carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and arabic gum; (d) wetting agent, for example glycerol; (e) disintegrating agent, for example agar, calcium carbonate, Rhizoma Solani tuber osi or tapioca, alginic acid, some composition silicates and sodium carbonate; (f) stripping blocker, for example paraffin; (g) absorption enhancer, for example quaternary ammonium compounds; (h) wetting agent, for example spermol and glyceryl monostearate; (i) absorbent, for example Kaolin and bentonite; And j) lubricant, for example Pulvis Talci, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulphate or its mixture.With regard to capsule, tablet and pill, dosage form can also comprise buffer agent.
Be used for Orally administered liquid dosage form and comprise the acceptable Emulsion of pharmacy, solution, suspension, syrup and elixir.Except that Candesartan or Candesartan Cilexetil, liquid dosage form can also comprise the inert diluent that is generally used for this area, for example water or other solvents, solubilizing agent and emulsifying agent.Typical emulsifying agent is ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propylene glycol, 1,3 butylene glycol, dimethyl formamide, the oil for example fatty acid ester of Oleum Gossypii semen, Oleum Arachidis hypogaeae semen, maize embryo oil, olive oil, Oleum Ricini and Oleum sesami, glycerol, tetrahydrofurfuryl alcohol, Polyethylene Glycol, sorbitan or the mixture of these materials etc.
Except this inert diluent, compositions can also comprise adjuvant, for example wetting agent, emulsifying agent and suspending agent, sweeting agent, correctives and aromatic.
Compare with the Candesartan Cilexetil dosage form of routine, pharmaceutical composition of the present invention shows the dosage/onset fast of the absorption of the lipotropy/bioavailability/increase that improves and the side effect of dissolution rate/minimizing/reduce.
The invention still further relates to new Candesartan disclosed herein and Candesartan Cilexetil nano-particle and can be used as the hypertensive method of treatment.
The preferred feature of Candesartan A. of the present invention and Candesartan Cilexetil nano-particle
1. the bioavailability that increases
Propose nano-particle candesartan cilexetil ester composition of the present invention, demonstrate the bioavailability that increases than the candesartan cilexetil ester formulation of routine and need be than the existing known dosage that lacks.
Embodiment 1:
The body giving drugs into nose of male Sprague-Dawley rat under fasted conditions is for dynamic test: the comparison of the Candesartan Cilexetil of reference active pharmaceutical ingredient and nanostructured
Experimental program
Comparison body giving drugs into nose in the male Sprague-Dawley rat under the fasted conditions is for dynamic test
The single port clothes dosage of reference Candesartan Cilexetil is that the single port clothes dosage of the candesartan cilexetil ester formulation of 10mg/kg and nanostructured is 53.3mg/kg, is equivalent to the 10mg/kg activating agent.Two samples all are to give through the administration volume of stomach tube with 5ml/kg.The vehicle of test event is aseptic 0.9%naCl solution, and through continuous stirring in therapeutic process suspension is kept evenly so that will reduce to minimum because of the error that deposition causes.
Animal
Under the controlled condition of temperature and illumination, give male Wistar rat (available from Laboratory Animal Center; University of Szeged) keeps standard pill appearance rodent diet (Bioplan Ltd; Isaszeg, Hungary), animal can arbitrarily obtain tap water.Laundering period was at least 4 days.Rat is divided into the groups of 6 animals at random, and every group is used for different time after the Candesartan Cilexetil treatment blood-sample withdrawal during time limit.Before oral medication with all animals fasting 16 hours.Use the halothane anesthesia animal, Candesartan Cilexetil treatment back was passed through heart puncturing extracting blood in 15,30,45,60,120 and 360 minutes.Make all animals obtain water at once after the treatment.Rat in the group (putting to death at 360min) obtained the standard rodent diet in back 120 minutes in treatment at last.Blood serum sample (7000rpm, 10min, 4 ℃) through centrifugal preparation blood coagulation in 60 minutes, and be stored in-20 ℃ till analyzing.
Sample preparation
Merging is used for protein precipitation with 1.2ml methanol with mark working solution in the aliquot of 200 μ l serum and the 20 μ l.With this mixture spiral 1min, and at 4 ℃ with the centrifugal 10min of 12000rpm.In nitrogen current, evaporate supernatant to doing, with 200 μ l water-methanols (50: 50v/v) dissolve again, 20 μ l are injected the HPLC system at 40 ℃.Use by Candesartan Cilexetil through enzyme hydrolysis prepare that Candesartan sets up standard curve confirm serum Candesartan concentration.
Statistical analysis
(GraphPad Software, San Diego USA) carry out statistical analysis and diagram to use GraphPad Prism 4.0.
The result
The treatment of the Candesartan Cilexetil of reference active medicine and nanostructured causes 15-360min behind the active sample of Orally administered 10mg/kg all to show the detected serum-concentration of two-phase characteristic at interval.Candesartan Cilexetil absorbs obviously than uses from the preparation of nanostructured behind the reference material sooner and is more complete.After the Candesartan Cilexetil treatment of nanostructured, the maximum serum-concentration (C of Candesartan
Max) be 7.071 ± 1.152 μ g/ml, and reference preparation is 1.612 ± 0.248 μ g/ml.In addition, observe C at time point early
Max(preparation of reference preparation and nanostructured is respectively t
Max =120min and 30min).
Calculate serum-concentration area under a curve (AUC between the 15-360min
15-360min) to characterize the degree of absorption that absorbs test event.Since the very fast absorption of nanometer size preparation, (AUC between 15-120min
15-120min) identical parameters calculated characterizes early stage exposed amount.The AUC of the preparation of reference compound and nanostructured
15-360minBe respectively 420.2 μ g*min/ml and 677.3 μ g*min/ml, AUC
15-120minBe 120.8 μ g*min/ml and 495.2 μ g*min/ml.Ratio (the AUC of two AUC values during the whole research
15-360min (nanometer particle size)/ AUC
15-360min (reference preparation)) be 1.6, and 2 hours (AUC of treatment beginning
15-120min (nanometer particle size)/ AUC
15-120min (reference preparation)) be 4.1 (Fig. 1).
Fig. 1: Orally administered 10mg/kg nanostructured with reference sample after the serum-concentration of Candesartan Cilexetil
2. the dissolution characteristic of nano-particle candesartan cilexetil ester composition of the present invention
Nano-particle Candesartan of the present invention and candesartan cilexetil ester composition form dissolubility and the dissolution characteristic with increase because of the granule of the granularity that reduces and unique nanostructured.The quick stripping of the activating agent of using is preferred, because stripping is fast more, generally causes onset faster and bioavailability is high more.
Embodiment 2:
Experimental program
Solubility test (C
Max)
Under 254nm wavelength and room temperature, measure Candesartan Cilexetil dissolubility in distilled water that nanostructured is confirmed to compare with reference API in (Agilent 8453) through UV-VIS.Filter the sample of redispersion through the disposable injection filter of 0.20 μ m.In order to check the nano-particle that exists in the solution, be used in the red laser indicator irradiation of operation under the 670nm wavelength.If do not observe scattering, it is successful then filtering, and this solution does not contain nano-particle.
Dissolution test
Through 5mg reference Candesartan Cilexetil and the Candesartan Cilexetil powder redispersion that comprises the 26.6mg nanostructured of 5mg Candesartan Cilexetil are carried out dissolution test in the 10mL distilled water.This suspension was stirred 1,5,10,15,20 and 30 minute, then it is filtered with the disposable injection filter of 0.2 μ m.Measure the candesartan cilexetil ester concentration with UV-VIS spectrophotometer (Agilent 8453).
The result
C
MaxMensuration
Carry out the dissolubility of redispersibility test with the Candesartan Cilexetil of mensuration nanostructured.The granularity of the Candesartan Cilexetil of the nanostructured of redispersion is 479nm in the meansigma methods based on intensity, be 422nm during in the digital averaging value.Based on intensity to be respectively d (90) value with the digital averaging value be 627 and 547nm.The dissolubility of the Candesartan Cilexetil of nanostructured is 0.4836mg/mL (Fig. 2).
Fig. 2.: the dissolubility of Candesartan Cilexetil strengthens
The contrast dissolution test
Because the instantaneous redispersibility of the Candesartan Cilexetil of the nanostructured of embodiment 6 is so the candesartan cilexetil ester content of the compositions more than 25% dissolves when redispersion at once.In 10 minutes, the particulate solution that comprises the nanostructured of redispersion reaches its saturation, and dissolved candesartan cilexetil ester content is 0.4836mg/mL, and the dissolubility of the Candesartan Cilexetil of itself and nanostructured has good correlation (Fig. 3 .).
Can not detect the reference candesartan cilexetil ester content in the distilled water through the UV-VIS method.
Fig. 3: the contrast dissolution test 3. of the Candesartan Cilexetil of reference Candesartan Cilexetil and nanostructured is through the dissolubility of amorphous/partially crystallizable/crystallization/polymorphic/cocrystallization form increase of nano-particle candesartan cilexetil ester composition of the present invention
The crystal habit of medicine influences the chemical stability of solid drugs.A lot of drug substances show polymorphism.Every kind of crystal habit has different chemical reactivities.Medicine generally is lower than the stability of medicine under its crystal habit in the stability under its amorphous form, and this is owing to the higher free energy level of amorphous state.
Can bring the chemical stabilizer of solid drugs to reduce with mechanical stress, for example grind to change crystal habit.
The crystal habit that is produced by difference in surface areas that the chemical stability of solid drugs also receives medicine influences.With regard on the medical solid surface, reacting, the increase of surface area can increase the amount of the medicine of participating in reaction.
Embodiment 3:
Crystal structure determination
The candesartan cilexetil ester composition of the partially crystallizable that the present invention is stable, crystallization, polymorphic or amorphous nanostructured shows obvious enhanced dissolubility because of its surface area increases with the comparison of crystallization reference substance the time.
Through the Candesartan Cilexetil nanoparticle structure of X-ray diffraction analysis (Philips PW1050/1870RTG powder diffraction meter) research through the preparation of the constant current nanometer sedimentation method.Measuring the candesartan cilexetil ester composition that shows nanostructured is partially crystallizable or amorphous (in Fig. 4).The characteristic reflection of crystallization Candesartan Cilexetil can be found in the XRD diffraction pattern of the big or small Candesartan Cilexetil of nanometer, and (Fig. 4 a) but have lower intensity.
Fig. 4: the x-ray diffraction pattern of the candesartan cilexetil ester composition of reference Candesartan Cilexetil and nanostructured
4. the redispersion characteristic of nano-particle candesartan cilexetil ester composition of the present invention
Another characteristic of nano-particle candesartan cilexetil ester composition of the present invention is can be through instantaneous or use the for example surfactant of mannitol, sucrose redispersion/polymer stabilizing drying nano granule of traditional redispersion agent.
Embodiment 4:
Be scattered in the redispersion of accomplishing the Candesartan Cilexetil powder of nanostructured in the 5mL distilled water through Candesartan Cilexetil powder with the 5mg nanometer particle size.After distilled water being made an addition in the powder of solid nano structure,, produce the particulate aqueous colloidal dispersion of Candesartan Cilexetil of nanostructured, just as shown in Figure 5 with the light jolting bottle of have gentle hands.Particulate granularity of redispersion and particle size distribution can be found out in Fig. 6.
Fig. 5: the instantaneous redispersibility of the Candesartan Cilexetil of nanostructured in distilled water
Fig. 6: the absorption of the candesartan cilexetil ester composition of the granularity of the Candesartan Cilexetil nano-particle before and after the redispersion and particle size distribution 5. increases nano-particleization of the present invention and the enhanced lipotropy of Penetration Signature
Because the phospholipid character of cell membrane; So lipotropy to a certain degree is the requirement of medical compounds normally; Intestinal wall after being not only administered through oral and using absorbs, and can in target tissue, bring into play its pharmacotoxicological effect people/Advanced Drug Delivery Reviews 59 (2007) 631-644 such as () F.Kesisoglou.
Can be through using the lipotropy stabilizing agent or/and on main polymer chain, have the stabilizing agent of lipotropy side group and/or the lipotropy that the amphiphilic stabilizing agent in the nanometer precipitation process increases Candesartan and Candesartan Cilexetil.Because the lipotropy or the lipotropy side group of applied stabilizing agent, so Candesartan of the present invention and Candesartan Cilexetil nano-particle not only can obtain increase aspect lipotropy but also absorption and the permeability.
For example, use chitosan, can increase the other permeability of enterocyte, this absorbs enhancing owing to striding film.
The most of amphipathic copolymer that is used to pass the medicine purpose comprises polyester or gathers (aminoacid)-derivant as hydrophobic segment.Most of polyethers that medicine is paid close attention to belongs to poloxamer family, i.e. the block copolymer of polypropylene glycol and Polyethylene Glycol.
6. the very fast surface wettability characteristic of nano-particle candesartan cilexetil ester composition of the present invention
In order to make the dissolving of Candesartan and Candesartan Cilexetil, its surface at first must be moistening by environment liquid.Amorphous/crystalline/the polymorphs form of nanometer size has chemical random surface, and its expression can cause the wettability improvement because of the hydrophobic and aqueous favoring mutual effect that stabilizing agent and active pharmaceutical ingredient character cause.If Candesartan of the present invention and Candesartan Cilexetil nano grain surface are functionalized by hydrophilic radical/stabilizing agent, it is very fast and stripping is very fast that then the hydrophilic of higher degree causes comparing with original crystal formation surface wettability.This advanced feature of Candesartan of the present invention and Candesartan Cilexetil nano-particle obtains the redispersibility result of the test and supports (referring to Fig. 4).Because the hydrophilic radical of bigger surface area, polymorphic character and the stabilizing agent (for example poloxamer-Pluronic PE10500) of nano-particle is so surface wettability is faster than crystal formation.
B. compositions
The invention provides the Candesartan of nanometer size and the granule of Candesartan Cilexetil nanostructured and form, it comprises at least a stabilizing agent, so that they are stable aspect space and/or static.
Stabilizing agent preferably associates with Candesartan and Candesartan Cilexetil or interacts with it, but not with Candesartan and Candesartan Cilexetil or self generation chemical reaction.
Can form the nano-particle of Candesartan of the present invention and Candesartan Cilexetil through solvent-anti-solvent precipitation, use stabilizing agent.Can increase the colloid solution stability of the Candesartan and the Candesartan Cilexetil of prepared nanometer size through merging other stabilizing agent, described other stabilizing agent can be used as second kind of space or the electrostatic stabilization agent is worked.In addition, use other stabilizing agent can reduce and control the granularity of Candesartan of the present invention and Candesartan Cilexetil.
The granularity of Candesartan Cilexetil nano-particle
The present invention comprises the Candesartan Cilexetil nano-particle, and it has the particle mean size of passing through dynamic light scattering determination less than about 500nm.
So-called " less than the particle mean size of about 500nm " means when passing through above-mentioned technical measurement, and at least 90% Candesartan Cilexetil nano-particle has the granularity less than numeral/average strength, promptly less than about 500nm etc.
Embodiment 5:
In experimentation, use continuous flow reactor to prepare the Candesartan Cilexetil nano-particle based on microfluid.As starting soln, use the 200mg Candesartan Cilexetil and the 1g Pluronic PE10500 of the mixed solvent that is dissolved in 90mL DMSO and 10mL distilled water.Use solution that feed pieces makes preparation to pass through reactor parts with the flow velocity of 1mL/min.Simultaneously, use second feed pieces, make distilled water pass through hydrid component, it is mixed with the solution that comprises Candesartan Cilexetil that derives from first reaction part with the flow velocity of 1.5mL/min.Cause causes under atmospheric pressure producing continuously nano-particle through the chemical precipitation of the water generates of hydrid component.The colloid solution that is produced is driven through second reaction part, begins to contact the dynamic light scattering parts (Nanotrac) integrated with this device, the granularity of the nano-particle that this can continuous detecting obtains.Can be through changing flow velocity, pressure and stabilizer types in wide region inner control nano-particle size (referring to Fig. 7).Can come accurately control particulate granularity of Candesartan Cilexetil and particle size distribution through flow velocity, as shown in Figure 8.The particulate granularity of Candesartan Cilexetil is 162nm under optimal cases.
Fig. 7: granularity and the particle size distribution of using the Candesartan Cilexetil nano-particle of different stabilizers.
Fig. 8: flow velocity is to the influence of the granularity and the particle size distribution of Candesartan Cilexetil nano-particle.
Embodiment 6:
In experimentation, use continuous flow reactor to prepare the Candesartan Cilexetil nano-particle based on microfluid.As starting soln, use is dissolved in the alcoholic acid 200mg Candesartan Cilexetil of 100mL and 600mg gathers (vinylpyrrolidone) PVP10.Use solution that feed pieces makes preparation to pass through reactor parts with the flow velocity of 2mL/min.Simultaneously, use second feed pieces, make 0.05% sodium acetate that is dissolved in the distilled water with the flow velocity of 8mL/min through hydrid component, it is mixed with the solution that comprises Candesartan Cilexetil that derives from first reaction part.Cause causes under atmospheric pressure producing continuously nano-particle through the chemical precipitation of the water generates of hydrid component.The colloid solution that is produced is driven through second reaction part, arrives the dynamic light scattering parts (Nanotrac) integrated with this device, the granularity of the nano-particle that this can continuous detecting obtains.Can be big or small at wide region inner control nano-particle through the type that changes flow velocity and stabilizing agent.Can pass through particulate granularity of flow speed control Candesartan Cilexetil and particle size distribution, as shown in Figure 9.The particulate granularity of Candesartan Cilexetil is 406nm (seeing table 1) under optimal cases.
Fig. 9: flow velocity is to the influence of the granularity and the particle size distribution of Candesartan Cilexetil nano-particle
Table 1: flow velocity is to the influence of Candesartan Cilexetil granularity
Embodiment 7:
The cream of load Candesartan Cilexetil nano-particle
In order to prepare the 100mL gel that comprises the Candesartan Cilexetil nano-particle, 1.3g carbopol 971 is dissolved under vigorous stirring as in through the synthetic 100mL Candesartan Cilexetil of method colloid solution described in the embodiment 6 in room temperature.
Claims (28)
1. the Candesartan of nanostructured, the acceptable ester of its pharmacy, preferred Candesartan Cilexetil and cocrystallization, it has the particle mean size less than about 500nm.
2. according to Candesartan, the acceptable ester of its pharmacy, preferred Candesartan Cilexetil and the cocrystallization of the nanostructured of claim 1, wherein said particle mean size is 500nm-50nm.
3. according to the Candesartan of the nanostructured of claim 1, wherein said particle mean size is 500nm-50nm.
4. according to the candesartan Cilexetil of the nanostructured of claim 1, preferred Candesartan Cilexetil, wherein said particle mean size is 500nm-50nm.
5. the compositions of stabilized nano structure, it comprises:
(a) have Candesartan or the acceptable ester of its pharmacy, preferred Candesartan Cilexetil or cocrystallization less than the nanostructured of the particle mean size of about 500nm; With
(b) at least a stabilizing agent.
6. according to the compositions of the stabilized nano structure of claim 3, it comprises:
(a) have Candesartan or the acceptable ester of its pharmacy, preferred Candesartan Cilexetil or cocrystallization less than the nanostructured of the particle mean size of about 500nm; With
(b) at least a stabilizing agent,
Wherein in continuous flow reactor, prepare compositions.
7. according to the compositions of the stabilized nano structure of claim 4, it comprises:
(a) have Candesartan or the acceptable ester of its pharmacy, preferred Candesartan Cilexetil or cocrystallization less than the nanostructured of the particle mean size of about 500nm; With
(b) at least a stabilizing agent,
Wherein in reaction vessel, prepare compositions based on microfluid.
8. according to the compositions of claim 6-8, it comprises and has the Candesartan that particle mean size is the nanostructured of 500nm-50nm.
9. according to the compositions of claim 6-8, it comprises and has the Candesartan Cilexetil that particle mean size is the nanostructured of 500nm-50nm.
10. according to the compositions of claim 6-10; Wherein: (a) amount of Candesartan or the acceptable ester of its pharmacy, preferred Candesartan Cilexetil or cocrystallization be selected from that about 99.5%-is about 0.001%, about 95%-about 0.1% and about 0.5% weight of about 90%-; Sum total and weight with Candesartan or the acceptable ester of its pharmacy, preferred Candesartan Cilexetil or cocrystallization and at least a stabilizing agent are benchmark, do not comprise other excipient; (b) amount of stabilizing agent is selected from about 99.999% weight of about 0.5%-, about 99.9% weight of about 5.0%-and about 99.5% weight of about 10%-; Total merging dry weight with Candesartan or the acceptable ester of its pharmacy, preferred Candesartan Cilexetil or cocrystallization and at least a stabilizing agent is a benchmark, does not comprise other excipient; Or (c) (a) and combination (b).
11. according to the compositions of claim 6-12, wherein, Candesartan or the acceptable ester of its pharmacy, preferred Candesartan Cilexetil or cocrystallization are selected from crystalline phase, amorphous phase, half hitch crystalline phase, half amorphous phase, cocrystallization and any polymorphous mixture thereof.
12. the compositions of claim 1-12 comprises as stabilizing agent: hydroxypropyl emthylcellulose, CAP, hydroxypropyl cellulose, gather (vinylpyrrolidone), sodium lauryl sulphate, gelatin, glucosan, stearic acid, glyceryl monostearate, cetostearyl alcohol, sorbitan ester, castor oil derivatives, based on the polymer that gathers (methyl) acrylic ester and copolymer, with vinyl-acetic ester polymer (PVP/VA copolymer), dodecylbenzene sodium sulfonate, tocopherol polyethyleneglycol succinate class, GREMAPHOR GS32 and derivant thereof, the polyoxyethylene sorbitan fatty acid ester of l-vinyl-2-pyrrolidone; Polyethylene glycols, Myrj 45 class, methylcellulose, hydroxyethyl-cellulose, polyvinyl alcohol, with the 4-(1 of oxirane and formaldehyde; 1; 3; The 3-tetramethyl butyl)-and cascophen class, poloxamer, polyamine class, it is derived from four functional blocks copolymers of addition expoxy propane and oxirane to ethylenediamine continuously; PEG-phospholipid, PEG-cholesterol, PEG-cholesterol derivative, PEG-vitamin A, PEG-vitamin E, lysozyme, gather (2-ethyl-2-oxazoline), gather the randomcopolymer of (methyl vinyl ether), vinyl pyrrolidone and vinylacetate.
13. the compositions of claim 1-13; It comprises hydroxypropyl cellulose derivant as other stabilizing agent, other stabilizing agent arbitrarily, two kinds of stabilizing agents of preferred claim 9 and/or chlorination dodecyl trimethyl ammonium, chlorination alkyl benzyl ammonium methyl, bromination alkyl benzyl dimethyl ammonium, bromination benzyltrimethylammon.um, benzalkonium chloride, cetyl trimethyl ammonium bromide.
14. the method for preparing according to Candesartan or the acceptable ester of its pharmacy, preferred Candesartan Cilexetil or the cocrystallization of the nanostructured of claim 1-14 comprises: if desired in the presence of acceptable acid of pharmacy or alkali in continuous flow reactor from the suitable solution of the Candesartan that comprises one or more stabilizing agents or the acceptable ester of its pharmacy, preferred Candesartan Cilexetil the Candesartan of deposition nanostructured or the acceptable ester of its pharmacy, preferred Candesartan Cilexetil.
15., use continuous flow reactor based on microfluid as continuous flow reactor according to the method for claim 15.
16. the method according to claim 15-16 comprises: (1) is dissolved in suitable solvent with Candesartan or the acceptable ester of its pharmacy, preferred Candesartan Cilexetil and one or more optional stabilizing agents;
(2) will join from the preparation of step (1) and comprise one or more stabilizing agents and medicine if desired
Learn in the solution of acceptable acid or alkali; (3) deposition is from the preparation of step (2).
17. the method according to claim 15-16 comprises: (1) is dissolved in suitable solvent with Candesartan or the acceptable ester of its pharmacy, preferred Candesartan Cilexetil and one or more stabilizing agents; (2) will join from the preparation of step (1) and comprise one or more optional stabilizing agents and if desired in the solution of the acceptable acid of pharmacy or alkali; (3) deposition is from the preparation of step (2).
18. the method according to claim 15-18 comprises: (a) use and to be prone to two kinds of miscible different solvents each other, wherein Candesartan or the acceptable ester of its pharmacy, preferably Candesartan Cilexetil be only soluble in they one of; Or (b) in two steps, use identical solvent, wherein Candesartan or the acceptable ester of its pharmacy, preferred Candesartan Cilexetil or cocrystallization form the granule of nanostructured, in fact, are restricted to applied stabilizing agent and are dissolved in used solvent.
19. pharmaceutical composition, it comprises according to the Candesartan of the nanostructured of claim 1-19 or the acceptable ester of its pharmacy, preferred Candesartan Cilexetil or cocrystallization and the optional acceptable auxiliary material of pharmacy.
20. the pharmaceutical composition of claim 20 wherein is mixed with said composition: (a) be used to be selected from oral, lung, rectum, colon, parenteral, the brain pond, intravaginal, intraperitoneal, eye, ear, part, suck, the using of nose and local application; (b) be selected from liquid dispersion, gel, aerosol, ointment, cream, lyophilized formulations, tablet, capsular dosage form; (c) dosage form that be selected from controlled release preparation, fast thawing preparation, time-delay delivery formulations, prolongs delivery formulations, pulsed delivery formulations and blended rapid release and controlled release preparation; Or (d) (a) and (b) and (c) combination in any.
21. to the Therapeutic Method of the individuality of needs, Candesartan or the acceptable ester of its pharmacy, preferred Candesartan Cilexetil or the cocrystallization of the nanostructured of the claim 1-19 through it being used effective dose carry out.
22. the Candesartan of the nanostructured of claim 1-19 or the acceptable ester of its pharmacy, preferred Candesartan Cilexetil or cocrystallization are used for preparing the purposes of medicine.
23. claim 1-19's has in water at least about the Candesartan of the nanostructured of the dissolubility of 0.4836mg/ml or the acceptable ester of its pharmacy, preferred Candesartan Cilexetil or cocrystallization are used for treating hypertensive dosage in reduction purposes.
24. the Candesartan of the nanostructured that in Physiological Medium, has instantaneous redispersibility of claim 1-19 or the acceptable ester of its pharmacy, preferred Candesartan Cilexetil or the purposes of cocrystallization in treatment hypertension.
25. Candesartan or the acceptable ester of its pharmacy, preferred Candesartan Cilexetil or the cocrystallization in the nanostructured of food that has minimizing under the dosage that reduces and side effect of claim 1-19 are being treated the purposes in the hypertension.
26. the Candesartan of the nanostructured of the absorption that in the human gastrointestinal tract, has increase of claim 1-19 or the acceptable ester of its pharmacy, preferred Candesartan Cilexetil or cocrystallization are used for treating the purposes of hypertensive dosage in reduction.
27. claim 1-19's has more Candesartan or the acceptable ester of its pharmacy, preferred Candesartan Cilexetil or the purposes of cocrystallization in treatment hypertension of the nanostructured of quick acting under the dosage that reduces.
28. Candesartan or the acceptable ester of its pharmacy, preferred Candesartan Cilexetil or the purposes of cocrystallization in treatment hypertension of claim 1-19 in the nanostructured of the variability that has minimizing under the dosage that reduces.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU0900376A HUP0900376A2 (en) | 2009-06-19 | 2009-06-19 | Nanoparticulate candesartan cilexetil composition |
| HUP0900376 | 2009-06-19 | ||
| PCT/HU2010/000073 WO2010146409A2 (en) | 2009-06-19 | 2010-06-18 | Nanoparticulate candesartan cilexetil compositions, process for the preparation thereof and pharmaceutical compositions containing them |
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| Publication Number | Publication Date |
|---|---|
| CN102791256A true CN102791256A (en) | 2012-11-21 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN2010800362962A Pending CN102791256A (en) | 2009-06-19 | 2010-06-18 | Nanoparticulate candesartan cilexetil compositions, process for the preparation thereof and pharmaceutical compositions containing them |
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| Country | Link |
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| US (1) | US20120141561A1 (en) |
| EP (1) | EP2442796A2 (en) |
| JP (1) | JP2012530127A (en) |
| CN (1) | CN102791256A (en) |
| AU (1) | AU2010261512A1 (en) |
| HU (1) | HUP0900376A2 (en) |
| IL (1) | IL217053A0 (en) |
| RU (1) | RU2012101816A (en) |
| SG (1) | SG176912A1 (en) |
| WO (1) | WO2010146409A2 (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106456780A (en) * | 2014-02-14 | 2017-02-22 | 成药技术Ip控股有限公司 | Complexes of sirolimus and derivatives thereof, process for preparing the same and pharmaceutical compositions containing the same |
| CN106977496A (en) * | 2017-03-13 | 2017-07-25 | 威海迪素制药有限公司 | A kind of crystallization preparation method of candesartan Cilexetil |
| CN107205931A (en) * | 2014-08-01 | 2017-09-26 | 安邦国际有限公司 | The method that the other amorphous solid dispersion of submicron order is prepared by co-precipitation |
| CN110638764A (en) * | 2019-09-23 | 2020-01-03 | 珠海润都制药股份有限公司 | Candesartan cilexetil quick-release pellet |
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| WO2010102066A1 (en) | 2009-03-05 | 2010-09-10 | Bend Research, Inc. | Dextran polymer powder for inhalation administration of pharmaceuticals |
| HUP1000325A2 (en) | 2010-06-18 | 2012-01-30 | Druggability Technologies Ip Holdco Jersey Ltd | Nanostructured aprepitant compositions and process for their preparation |
| US9084727B2 (en) | 2011-05-10 | 2015-07-21 | Bend Research, Inc. | Methods and compositions for maintaining active agents in intra-articular spaces |
| WO2015071841A1 (en) | 2013-11-12 | 2015-05-21 | Druggability Technologies Holdings Limited | Complexes of dabigatran and its derivatives, process for the preparation thereof and pharmaceutical compositions containing them |
| KR102304910B1 (en) * | 2021-01-11 | 2021-09-27 | 알리코제약(주) | Stable pharmaceutical composition comprising candesartan |
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Also Published As
| Publication number | Publication date |
|---|---|
| AU2010261512A1 (en) | 2012-02-09 |
| RU2012101816A (en) | 2013-07-27 |
| WO2010146409A2 (en) | 2010-12-23 |
| SG176912A1 (en) | 2012-01-30 |
| EP2442796A2 (en) | 2012-04-25 |
| HUP0900376A2 (en) | 2011-01-28 |
| IL217053A0 (en) | 2012-02-29 |
| HU0900376D0 (en) | 2009-08-28 |
| US20120141561A1 (en) | 2012-06-07 |
| WO2010146409A3 (en) | 2011-09-09 |
| JP2012530127A (en) | 2012-11-29 |
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